“This is scary and we don’t know…” “We don’t know the timing of the next pandemic, how severe it will be. We don’t know what drugs will work. We don’t have a vaccine. Yet we are telling everyone to prepare for a pandemic. It’s tricky…This is scary and we don’t know…that’s the message.” Dick Thompson World Health Organization December 2005

INFLUENZA - the name Influenza is Italian for "influence", Latin: influentia. It used to be thought that the disease was caused by a bad influence from the heavens.

Flu sometimes is confused with the common cold Flu sometimes is confused with the common cold. However, the flu is caused by influenza virus, and is a much more severe disease than the common cold, which is caused by a different type of virus. Influenza is a more severe viral infection of the respiratory tract that shows the additional symptoms to those of the common cold (rapidly rising fever, chills, and body and muscle aches).

INFLUENZA

Influenza is an acute systemic viral disease. Has very serious complications. Caused by influenza virus.

Classification \Family is Orthomyxoviridae Influenza family which is subdivided into 3 genera: A, B, and C, based on antigenic differences in the nucleoprotein (NP) and matrix (M) protein. 2. Influenza A viruses are further characterized by antigenic differences associated with the Haemagglutinin (HA) and Neuraminidase (N) glycoproteins; there are at least 15 subtypes of H and 9 subtypes of N proteins in influenza A virus. 3. All subtypes have been described in birds and some of them have been found in mammals.

Type A Type B Type C Humans Humans Swine Birds Horses Seals Humans Because of A’s ability to infect numerous carriers, it is the most dangerous subtype, and will be focus of presentation. Dangerous outbreaks are often the result of genetic reassortment, which relies on cross infection of one host with more than one strain of the virus, followed by transmission from one species to humans. This can’t happen with B, so there are less outbreaks. Humans Swine

Virus characteristics Virion is 80-120 nm in diameter), enveloped, spherical to slightly pleomorphic in shape. Underline the envelope is the Matrix ( M1 & M2) 2. Genome consists of 8 segments of ss RNA in A& B and 7 segments in C 3. The envelope contains 2 glycoproteins: H (hemagglutinin), and N (neuraminidase) 4. associated with the genome is nucleoprotein (NP)

ORTHOMYXOVIRUSES HA - hemagglutinin NA - neuraminidase M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase Type A, B, C : NP, M1 protein Sub-types: HA or NA protein

Influenza virus A/Beijing/32/92 (H3N2) Hemagglutinin Neuraminidase Influenza type A viruses have a major name from the 2 surface proteins – H & N – and strain numbers from where the subtype is first discovered Neuraminidase A/Beijing/32/92 (H3N2) Virus type Geographic origin Strain number Year of Isolation Virus subtype

Influenza A is classified into subtypes based on HA & NA

DISEASE Influenza A virus cause Influenza B virus cause worldwide epidemics (pandemic) major outbreaks of influenza occurs virtually every year. Influenza B virus cause

Nomenclature A/equine/Prague/1/56(H7N7) A/fowl/Hong Kong/1/98(H5N1) A/equine/Saskatoon/1/90(H3N8) Serotype of HA and N group year species Isolate number location A/equine/Prague/1/56(H7N7) A/fowl/Hong Kong/1/98(H5N1) A/swine/Lincoln/1/86(H1N1)

Seasonal (human) Influenza ( H1N1) Endemic Strain varies slightly year to year Avian Influenza (H5N1) May be reservoir for completely new strains in humans Can be Highly Pathogenic Avian Influenza (HPAI) Pandemic Influenza (H1N1) Global epidemic of new influenza A subtype in humans Instructor: This slide is review if Modules 1 and 2 have already been completed. You may skip this slide or cover only briefly. Seasonal Influenza is human influenza. It is endemic worldwide and is seen at regular intervals annually. The same hemagglutinin type circulates around the globe year after year, mutating slightly as it goes. The result of these mutations is that over time, susceptibility is renewed because of changes in the surface proteins of the virus that allow it to evade the immunity built up by previous influenza infections. The season in which it occurs may be different in temperate climates, where it is a winter-time disease, and tropical climates where transmission probably occurs year round but is largely unstudied. Avian influenza is a disease of birds that can occasionally infect humans when there is significant exposure. Avian influenza viruses are thought to be the reservoir for new types of influenza viruses in humans that cause pandemics when they acquire the ability to circulate in humans. The factors that must be present to enable the virus to do this are unknown. Pandemic Influenza is a global epidemic of a new influenza A virus subtype that passes easily from person to person and causes severe disease. The emergence of a new human influenza A virus subtype occurs either through genetic reassortment or direct poultry to human transmission from an avian species with a virus that has acquired the ability to spread easily from human-to-human.

ANTIGENIC CHANGES Influenza viruses especially type A show changes in antigenicity of hemagglutinin (H) and neuraminidase (N) proteins. Antigenic shifts: major changes based on the reassortment of RNA segments. It occurs only with influenza A. Other theories of antigenic shift includes: Recirculation of existing subtypes Gradual adaptation of animal viruses to human transmission Antigenic drifts: minor changes based on mutations in the RNA genome.

Animal viruses (aquatic birds, chicken, swine) are the source of RNA segments that encode antigenic shift variants. Because influenza B virus is only a human virus, there is no animal source of new RNA segments. Influenza B virus shows only antigenic drift, but not shift.

Antigenic Variation Due to:- A. genome is segmented Can infect wild range of different species. It is RNA virus ( mutation more common). Two forms

1. Antigenic shift Major change. Occurs in influenza A only. Result in a new subtype. Associated with pandemic

Mechanism Co-infection with 2 different subtypes usually avian and human occurs in pigs ( mixing vessel) .(same cell 2 subtypes) Genetic reassortment occurs ( swapping of the genes) results in development of a new subtype

Reassortment

Pigs Serve As Mixing Vessels for reassortants Pig cells contain receptors for both human and avian viruses. Aquatic birds and domestic Pigs Human Poultry (Human virus) (Avian virus) Human (reassortant virus)

A / PHILIPPINES / 82 (H3N2) A group antigen of influenza A Philippines / 82 location and year the virus isolated H3N2 Hemagglutinin and Neuraminidase types H1N1 and H3N2 strains of influenza A are the most common types at this time and are the strains included in the current vaccine.

Past Antigenic Shifts 1918 H1N1 “Spanish Influenza” 20-40 million deaths 1957 H2N2 “Asian Flu” 1-2 million deaths 1968 H3N2 “Hong Kong Flu” 700,000 deaths 1977 H1N1 Re-emergence No pandemic At least 15 HA subtypes and 9 NA subtypes occur in nature. Up until 1997, only viruses of H1, H2, and H3 are known to infect and cause disease in humans.

2. Antigenic drift Minor change. Occurs in influenza A & B Occurs between epidemics. Results in seasonal localized outbreaks.

Mechanism Due to cumulative point mutations in the HA gene

Transmission Airborne – droplets – esp. crowded populations in enclosed spaces Direct contact – virus may persist on object for hours to days – esp. in cool, dry areas Incubation – 1 – 3 days Communicable – 1-2 days before onset of symptoms and 4-5 days after onset Possibly up to 21 days in < 12 y.o. or adults w/ avian

Influenza spread Influenza is spread by droplet, especially from coughing and sneezing Courtesy of Centers for Disease Control and Prevention

Clinical Features Incubation period 24 – 48 hours Sudden onset of fever with chills , myalgias, headache, dry cough, photophobia, sore throat Diarrhoea and vomiting may occur Resolve spontaneously in 4 – 7 days. although cough and malaise can persist for >2 weeks. Influenza B is similar to A, but influenza C is usually subclinical or milder in nature.

Complications Tend to occur in the young, elderly, pregnants persons with chronic cardio-pulmonary diseases. Persons with chronic diseases :DM,renal,liver Immunocompromized patients

COMPLICATIONS Tracheobronchitis and bronchiolitis Croup Primary viral pneumonia Secondary bacterial pneumonia usually occurs late in the course of disease, after a period of improvement has been observed for the acute disease. S. aureus is most commonly involved although S. pneumoniae and H. influenzae may be found. Myositis and myoglobinuria

Myocarditis and pericaditis Reye's syndrome Reye's syndrome is characterized by encephalopathy and fatty liver degeneration. It occurs in children with viral infection and are taken aspirin to reduce fever. The disease had been associated with several viruses; such as influenza A and B, Coxsackie B5, echovirus, HSV, VZV, CMV and adenovirus. Myocarditis and pericaditis

LABORATORY DIAGNOSIS Virus Isolation Specimens :Throat swabs, Nasopharyngeal aspirate (NPA) and nasal washings may be used for virus isolation.. Influenza viruses isolated from embryonated eggs or tissue culture can be identified by serological or molecular methods. Rapid Diagnosis by Immunoflurescence (Antigen detetection) cells from pathological specimens may be examined for the presence of influenza A and B antigens by indirect immunofluorescence. Nucleic acid detection using PCR ( same specimen as above)

Serology Demonstration of a rise in serum antibody to the infecting virus

TREATMENT Amantidine The only effective against influenza A. Act at the level of virus uncoating inhibit M2 protein. Both therapeutic and prophylactic effects. Significantly reduces the duration of fever (51 hours as opposed to 74 hours) and illness. 70% protection against influenza A when given prophylactically. Rimantadine is an amantadine derivative but not as effective as amantadine and less toxic.

Neuraminidase inhibitors - zanamivir (given by inhalation) - oseltamivir (orally) Used for influenza A and B including pandemic H1N1 Used for treatment and prophylaxis To be maximally effective the drugs must be administered very early in the disease.

Anti-viral drugs: General background Amantadine Rimantadine Zanamivir Oseltamivir Type of Influenza virus infection indicated for use Influenza A Influenza B Administration oral oral inhalation Ages approved for treatment of flu 1 year 14 year 7 years 18 years Ages approved for prevention of flu not approved http://www.tulane.edu/~dmsander/WWW/335/Orthomyxoviruses.html

PREVENTION Vaccine Protection lasts only 6 months Yearly boosters are recommended Should be given to people Older than 65 years With chronic respiratory diseases With chronic cardiovascular diseases. Immunity to Influenza Antibody against hemagglutinin (H) is the most important component in the protection against influenza viruses.

Influenza Vaccines Though existing vaccines are continually being rendered obsolete as viruses undergo antigenic drift and shift. Yet controlled trials of influenza vaccines indicate that a moderate degree of protection (50-80%) is attainable.

1) Inactivated influenza vaccines Is a trivalent vaccine containing (H1N1 ,H3N2 and B ) Vaccines are either whole virus (WV) vaccine which contains intact, inactivated virus or subvirion (SV) vaccine: contain purified HA and NA glycoproteins. .

2) Live influenza vaccines: The only feasible strategy to develop a live-virus vaccine is to devise a way to transfer defined attenuating genes from an attenuated master donor virus to each new epidemic or pandemic isolate. A cold-adapted influenza virus (able to grow at 25C but not at 37C) introduced intranasally should replicate in the nasopharynx but not in the lower respiratory tract, its multiplication stimulate the local production of IgA. ( Flumist)

Good luck

AVIAN INFLUENZA Avian influenza A viruses usually do not infect humans Rare cases of human infection with avian influenza viruses have been reported since 1997 with avian influenza A (H5N1) viruses All strains of the infecting virus were totally avian in origin and there was no evidence of reassortment. Infection in humans are thought to have resulted from direct contact with infected poultry or contaminated surfaces. To date, human infections with avian influenza A viruses have not resulted in sustained human-to-human transmission.

PICORNAVIRUSES

PICORNAVIRUSES Small (20 – 30 nm) non–enveloped viruses, with icosahedral nucleocapsid and ssRNA genome with positive polarity. Includes two groups: Enteroviruses Enteroviruses include poliovirus, coxsackieviruses, echovirus and hepatitis A virus. replicate optimally at 37 ºC Enteroviruses are stable under acid conditions (pH 3 – 5) Rhinoviruses Rhinoviruses grow better at 33 ºC in accordance with the lower temperature of the nose. Rhinoviruses are acid – labile.

RHINOVIRUSES

RHINOVIRUSES Common cold accounts for 1/3 to 1/2 of all acute respiratory infections in humans. Rhinoviruses are responsible for 50% of common colds, coronaviruses for 10%, adenoviruses, enteroviruses, RSV, influenza, parainfluenza can also cause common cold symptoms indistinguishable form those caused by rhinoviruses and coronaviruses. Common cold is a self-limited illness. More than 100 serologic types of rhinoviruses (No vaccine)

TRANSMISSION Directly from person to person via respiratory droplets Indirectly in which droplets are deposited on the hands or on a surface such as table and then transported by fingers to the nose or eyes. An individual may suffer 2 to 5 episodes of colds per year. The primary site of rhinovirus infection is in the nasal epithelium. Rhinoviruses rarely cause lower respiratory infection.

CLINICAL FINDINGS Incubation period: 2 – 4 days Sneezing Nasal discharge Nasal obstruction Sore throat Cough Headache Lasts for 1 week

COMPLICATIONS Acute bacterial sinusitis Acute bacterial otitis media The major causes are Pneumococcus, Hemophilus influenza, Moraxella, and Staphylococci. Acute bacterial otitis media mainly a problem in children Asthma attacks in children Exacerbation of chronic bronchitis

LABORATORY DIAGNOSIS Usually, common cold does not require laboratory investigation Cell culture isolation from nasal secretion

TREATMENT Cold treatments recommended include the following: Antihistamines Nonsteroidal antinflammatory drugs Decongestants (vasoconstrictors) Cough suppressants (narcotics)

CORONAVIRUSES 

CORONAVIRUSES The group was so named because of the crown-like projections on its surface. At present, at least 10 species are recognized, of which human coronavirus is one. The other viruses are found in animals.

PROPERTIES ssRNA enveloped viruses of pleomorphic morphology 60 to 220nm in diameter. Positive stranded RNA; helical symmetry Three antigenic molecules are found in the virions i.e. nucleocapsid, surface projection and transmembrane proteins. The main antigenic determinants reside on the surface projections. Human coronavirus strains fall into serological groups, which are named OC43, and 229E.

EPIDEMIOLOGY Human coronavirus infections occur during the winter and early spring. High infection rates during the year are caused by either 229E or OC43 group viruses. This pattern is observed throughout the world. Human coronaviruses are responsible for 10 - 30% of all common colds.

DIAGNOSIS AND TREATMENT Laboratory diagnosis is not attempted. Coronaviruses have fastidious growth requirement in cell culture. No antiviral drugs against coronaviruses are available.

OTHER CAUSES OF COMMON COLD SYNDROME Coxsackievirus Herpangina (severe sore throat with vesiculoulcerative lesions) Pleurisy common cold syndrome Adenovirus Pharyngitis Bronchitis pneumonia (types 3, 4, 7 and 21) Influenza C

Definition of Terms Seasonal (human) Influenza Avian Influenza Endemic Strain varies slightly year to year Avian Influenza May be reservoir for completely new strains in humans Can be Highly Pathogenic Avian Influenza (HPAI) Pandemic Influenza Global epidemic of new influenza A subtype in humans Instructor: This slide is review if Modules 1 and 2 have already been completed. You may skip this slide or cover only briefly. Seasonal Influenza is human influenza. It is endemic worldwide and is seen at regular intervals annually. The same hemagglutinin type circulates around the globe year after year, mutating slightly as it goes. The result of these mutations is that over time, susceptibility is renewed because of changes in the surface proteins of the virus that allow it to evade the immunity built up by previous influenza infections. The season in which it occurs may be different in temperate climates, where it is a winter-time disease, and tropical climates where transmission probably occurs year round but is largely unstudied. Avian influenza is a disease of birds that can occasionally infect humans when there is significant exposure. Avian influenza viruses are thought to be the reservoir for new types of influenza viruses in humans that cause pandemics when they acquire the ability to circulate in humans. The factors that must be present to enable the virus to do this are unknown. Pandemic Influenza is a global epidemic of a new influenza A virus subtype that passes easily from person to person and causes severe disease. The emergence of a new human influenza A virus subtype occurs either through genetic reassortment or direct poultry to human transmission from an avian species with a virus that has acquired the ability to spread easily from human-to-human.

Three Types of Influenza Seasonal influenza refers to the periodic outbreaks of respiratory illness in the fall and winter. Avian influenza - also known as the bird flu - is caused by virus that infects wild birds and domestic poultry. Two types: Low pathogenic avian influenza virus (H5 and H7) and highly pathogenic avian or bird influenza of the H5N1 strain. Pandemic influenza refers to a worldwide outbreak of influenza among people when a new strain of the virus emerges that has the ability to infect humans and to spread from person to person.

What is seasonal flu? Contagious, respiratory illness Affects 5-20% of population each year Kills approximately 36,000 every year Can be prevented with a vaccine

Bird or Avian Flu – H5N1 A powerful virus Spread by migratory birds Transmitted from birds to humans and other mammals Kills 60% of its victims It continues to change -Why are we so concerned about pandemic flu now? -First, the last one was almost 40 years ago, in 1968, so we are due. -Second, there is a potential candidate out there that has the potential to be extremely deadly if it becomes a pandemic. -You have probably heard of H5N1, the bird flu or avian flu. -Avian flu occurs naturally in birds. -Since 1996, we have seen an increase in the number of H5N1 cases that have spread from bird to human. -Flu viruses are very smart and mutate in order to survive. -If the H5N1 mutates into a virus that can spread from human-to-human, we are likely to have a deadly pandemic on our hands.

H5N1 Transmission Bird  Human Human  Human Handling live diseased birds Preparing dead diseased birds Eating undercooked poultry Human  Human Rare 2004 Thailand 2006 Indonesia Takes a large inoculum, not very contagious Case contacts, HCW’s rare seroconversion – can’t exclude separate poultry exposure For seasonal flu, human to human transmission occurs from coughing/sneezing/talking via droplets, also hand to hand Courtesy of Dr. Steve Lawrence www.bbc.co.uk 66

What is Pandemic Influenza? An influenza pandemic occurs when a new influenza virus appears against which the human population has no immunity, resulting in several, simultaneous epidemics worldwide with enormous numbers of deaths and illness. -A virus to which people have little or no immunity. -It spreads easily and quickly from person to person. -It causes serious illness and even death. -This picture shows a mail carrier in Seattle during the 1918 pandemic.

How Influenza Can Spread Between People Influenza is thought to be primarily spread through large droplets (droplet transmission) that directly contact the nose, mouth or eyes. Droplets are produced when infected people cough, sneeze or talk, sending the relatively large infectious droplets and very small sprays (aerosols) into the nearby air and into contact with other people. Large droplets can only travel a limited range; therefore, people should limit close contact (within 6 feet) with others when possible.